Genetic mouse models of neurodegenerative disorders can provide valuable insight into the pathogenesis of the corresponding human condition, and can serve to address specific hypotheses about the biology of the relevant gene product in health and disease. Investigations into genes that cause inherited forms of Parkinson's disease (PD), the mechanisms involved in their cellular and molecular biology, as well as the downstream pathways that they trigger shed considerable light on our understanding the fundamental determinants of life and death in dopaminergic neurons. DJ-1 is one of five genes identified thus far to be definitely linked to inherited PD. The two original mutations identified in the DJ-1 locus in affected pedigrees are transmitted recessively suggesting loss of function. Although considerable knowledge about the anti- oxidant properties of DJ-1 has been generated, and its diverse functions in other systems have been studied, its role in the biology of dopaminergic neurons has been addressed in limited studies and remains poorly understood. Therefore, how DJ-1 protects cells and how its absence or point mutations result in dopamine neuronal death remain largely unanswered questions. To date, the cytoprotective activity of DJ-1 against oxidant damage has been attributed largely to its reactive oxygen species (ROS) quenching ability. However, our findings indicate that the ROS quenching potential of DJ-1 is weak compared to its robust cell preserving activity. Rather, our data point to an alternative mechanism for the cytoprotective function of DJ-1 which appears to have a critical role in inhibiting a specific kinase-mediated cell death-signaling pathway. The end result is protection against insults that activate this pathway, including oxidant damage. The pathogenic relevance of this proposed scheme in PD is strengthened by failure of a PD-causing DJ-1 mutant at each step of this pathway. This application proposes to investigate the in vivo validity of this hypothesis using a novel genetic mouse model. This proposal also addresses the relatively selective vulnerability of dopaminergic neurons to DJ-1 deletion despite its ubiquitous expression. For lay public: The goal of this project is to understand how mutations in DJ-1, a gene responsible for some forms of Parkinson's disease, cause degeneration of dopamine producing brain cells. Elucidating the steps in this process can help develop treatments that could block its progression. [unreadable] [unreadable] [unreadable]